Target Information
| Target General Information | Top | |||||
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| Target ID |
T73475
(Former ID: TTDR00029)
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| Target Name |
Matrix metalloproteinase-7 (MMP-7)
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| Synonyms |
Uterine metalloproteinase; Pump-1 protease; PUMP1; Matrin; Matrilysin; MPSL1
Click to Show/Hide
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| Gene Name |
MMP7
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Lung cancer [ICD-11: 2C25] | |||||
| Function |
Activates procollagenase. Degrades casein, gelatins of types I, III, IV, and V, and fibronectin.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.24.23
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| Sequence |
MRLTVLCAVCLLPGSLALPLPQEAGGMSELQWEQAQDYLKRFYLYDSETKNANSLEAKLK
EMQKFFGLPITGMLNSRVIEIMQKPRCGVPDVAEYSLFPNSPKWTSKVVTYRIVSYTRDL PHITVDRLVSKALNMWGKEIPLHFRKVVWGTADIMIGFARGAHGDSYPFDGPGNTLAHAF APGTGLGGDAHFDEDERWTDGSSLGINFLYAATHELGHSLGMGHSSDPNAVMYPTYGNGD PQNFKLSQDDIKGIQKLYGKRSNSRKK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T33KFW | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Prinomastat | Drug Info | Approved | Lung cancer | [2], [3] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Marimastat | Drug Info | Phase 3 | Pancreatic cancer | [4], [5] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | BMS 275291 | Drug Info | Discontinued in Phase 3 | Kaposi sarcoma | [6] | |
| 2 | BB-3644 | Drug Info | Terminated | Solid tumour/cancer | [7] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 13 Inhibitor drugs | + | ||||
| 1 | Prinomastat | Drug Info | [1], [8], [9], [10], [11] | |||
| 2 | Marimastat | Drug Info | [12], [13], [14], [11] | |||
| 3 | BMS 275291 | Drug Info | [6], [15], [16], [11] | |||
| 4 | BB-3644 | Drug Info | [11], [7] | |||
| 5 | 3-Benzenesulfonyl-heptanoic acid hydroxyamide | Drug Info | [17] | |||
| 6 | 3-Cyclohexanesulfonyl-heptanoic acid hydroxyamide | Drug Info | [17] | |||
| 7 | Folate gamma-hydroxamic acid | Drug Info | [18] | |||
| 8 | Folate gamma-L-phenylalaninehydroxamic acid | Drug Info | [18] | |||
| 9 | MMI270 | Drug Info | [18] | |||
| 10 | N-hydroxy-2,3-bis(phenylsulfonamido)propanamide | Drug Info | [19] | |||
| 11 | RS-39066 | Drug Info | [20] | |||
| 12 | SL422 | Drug Info | [21] | |||
| 13 | SR-973 | Drug Info | [22] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: 1,2-Dimyristoyl-sn-glycero-3-phosphocholine | Ligand Info | |||||
| Structure Description | NMR Solution Structure of the PRO Form of Human Matrilysin (proMMP-7) in Complex with Anionic Membrane | PDB:2MZI | ||||
| Method | Solution NMR | Resolution | N.A. | Mutation | Yes | [23] |
| PDB Sequence |
LPQEAGGMSE
9 LQWEQAQDYL19 KRFYLYDSET29 KNANSLEAKL39 KEMQKFFGLP49 ITGMLNSRVI 59 EIMQKPRCGV69 PDVAEYSLFP79 NSPKWTSKVV89 TYRIVSYTRD99 LPHITVDRLV 109 SKALNMWGKE119 IPLHFRKVVW129 GTADIMIGFA139 RGAHGDSYPF149 DGPGNTLAHA 159 FAPGTGLGGD169 AHFDEDERWT179 DGSSLGINFL189 YAATHALGHS199 LGMGHSSDPN 209 AVMYPTYGNG219 DPQNFKLSQD229 DIKGIQKLYG239 KRSNSRKK
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THR85
3.202
SER86
1.723
LYS87
1.627
VAL88
2.815
THR90
3.088
TYR91
3.224
ARG92
1.627
ILE93
3.841
VAL94
2.812
TYR96
3.561
ASP99
3.204
LEU100
3.172
PRO101
2.671
HIS102
2.418
ILE103
2.698
THR104
3.416
ASP106
3.096
ARG107
1.982
SER110
3.215
LYS111
2.451
LEU113
4.611
ASN114
1.936
MET115
3.486
GLY117
2.872
LYS118
1.842
GLU119
4.782
ILE120
3.387
PRO121
4.314
LEU122
3.229
HIS123
2.192
PHE124
1.851
ARG125
1.631
LYS126
1.778
VAL127
3.239
VAL128
2.544
TRP129
1.637
GLY130
2.507
THR131
3.090
ALA132
3.580
ASP133
4.210
MET135
3.906
ARG177
3.172
ASP180
4.104
GLY181
3.325
LEU184
3.983
LEU189
4.096
PRO221
4.580
GLN222
2.730
ASN223
1.867
PHE224
3.030
LYS225
1.669
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| Ligand Name: Cholesterol sulfate | Ligand Info | |||||
| Structure Description | NMR Solution Structure of the PRO Form of Human Matrilysin (proMMP-7) in Complex with Anionic Membrane | PDB:2MZI | ||||
| Method | Solution NMR | Resolution | N.A. | Mutation | Yes | [23] |
| PDB Sequence |
LPQEAGGMSE
9 LQWEQAQDYL19 KRFYLYDSET29 KNANSLEAKL39 KEMQKFFGLP49 ITGMLNSRVI 59 EIMQKPRCGV69 PDVAEYSLFP79 NSPKWTSKVV89 TYRIVSYTRD99 LPHITVDRLV 109 SKALNMWGKE119 IPLHFRKVVW129 GTADIMIGFA139 RGAHGDSYPF149 DGPGNTLAHA 159 FAPGTGLGGD169 AHFDEDERWT179 DGSSLGINFL189 YAATHALGHS199 LGMGHSSDPN 209 AVMYPTYGNG219 DPQNFKLSQD229 DIKGIQKLYG239 KRSNSRKK
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Wnt signaling pathway | hsa04310 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 9 | Degree centrality | 9.67E-04 | Betweenness centrality | 4.13E-04 |
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| Closeness centrality | 2.32E-01 | Radiality | 1.41E+01 | Clustering coefficient | 8.33E-02 |
| Neighborhood connectivity | 4.56E+01 | Topological coefficient | 1.40E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-regulating Transcription Factors | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Wnt signaling pathway | |||||
| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | Wnt Signaling Pathway | |||||
| Panther Pathway | [+] 3 Panther Pathways | + | ||||
| 1 | Alzheimer disease-presenilin pathway | |||||
| 2 | Wnt signaling pathway | |||||
| 3 | CCKR signaling map ST | |||||
| PID Pathway | [+] 3 PID Pathways | + | ||||
| 1 | Posttranslational regulation of adherens junction stability and dissassembly | |||||
| 2 | p75(NTR)-mediated signaling | |||||
| 3 | Syndecan-1-mediated signaling events | |||||
| Reactome | [+] 4 Reactome Pathways | + | ||||
| 1 | Collagen degradation | |||||
| 2 | Degradation of the extracellular matrix | |||||
| 3 | Activation of Matrix Metalloproteinases | |||||
| 4 | Assembly of collagen fibrils and other multimeric structures | |||||
| WikiPathways | [+] 4 WikiPathways | + | ||||
| 1 | Wnt Signaling Pathway and Pluripotency | |||||
| 2 | Activation of Matrix Metalloproteinases | |||||
| 3 | AGE/RAGE pathway | |||||
| 4 | Matrix Metalloproteinases | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | AG-3340 (Agouron Pharmaceuticals Inc). IDrugs. 2000 Mar;3(3):336-45. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6505). | |||||
| REF 3 | Emerging therapies for neuropathic pain. Expert Opin Emerg Drugs. 2005 Feb;10(1):95-108. | |||||
| REF 4 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5220). | |||||
| REF 5 | Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol. 2004 Dec 1;22(23):4683-90. | |||||
| REF 6 | Phase 1/2 trial of BMS-275291 in patients with human immunodeficiency virus-related Kaposi sarcoma: a multicenter trial of the AIDS Malignancy Consortium. Cancer. 2008 Mar 1;112(5):1083-8. | |||||
| REF 7 | A phase I and pharmacological study of the matrix metalloproteinase inhibitor BB-3644 in patients with solid tumours. Br J Cancer. 2004 Feb 23;90(4):800-4. | |||||
| REF 8 | Inhibition of gelatinase activity reduces neural injury in an ex vivo model of hypoxia-ischemia. Neuroscience. 2009 Jun 2;160(4):755-66. | |||||
| REF 9 | Delayed administration of a matrix metalloproteinase inhibitor limits progressive brain injury after hypoxia-ischemia in the neonatal rat. J Neuroinflammation. 2008 Aug 11;5:34. | |||||
| REF 10 | Pharmacoproteomics of a metalloproteinase hydroxamate inhibitor in breast cancer cells: dynamics of membrane type 1 matrix metalloproteinase-mediat... Mol Cell Biol. 2008 Aug;28(15):4896-914. | |||||
| REF 11 | Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006 Mar;6(3):227-39. | |||||
| REF 12 | Metalloelastase (MMP-12) induced inflammatory response in mice airways: effects of dexamethasone, rolipram and marimastat. Eur J Pharmacol. 2007 Mar 15;559(1):75-81. | |||||
| REF 13 | Matrix metalloproteinase-2 involvement in breast cancer progression: a mini-review. Med Sci Monit. 2009 Feb;15(2):RA32-40. | |||||
| REF 14 | Matrix metalloproteinase inhibition as a novel anticancer strategy: a review with special focus on batimastat and marimastat. Pharmacol Ther. 1997;75(1):69-75. | |||||
| REF 15 | Randomized phase II feasibility study of combining the matrix metalloproteinase inhibitor BMS-275291 with paclitaxel plus carboplatin in advanced non-small cell lung cancer. Lung Cancer. 2004 Dec;46(3):361-8. | |||||
| REF 16 | Randomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR.18. J Clin Oncol. 2005 Apr 20;23(12):2831-9. | |||||
| REF 17 | Hydroxamic acid derivatives as potent peptide deformylase inhibitors and antibacterial agents. J Med Chem. 2000 Jun 15;43(12):2324-31. | |||||
| REF 18 | Methotrexate gamma-hydroxamate derivatives as potential dual target antitumor drugs. Bioorg Med Chem. 2007 Feb 1;15(3):1266-74. | |||||
| REF 19 | Novel bis-(arylsulfonamide) hydroxamate-based selective MMP inhibitors. Bioorg Med Chem Lett. 2008 Jun 1;18(11):3333-7. | |||||
| REF 20 | Design, synthesis, activity, and structure of a novel class of matrix metalloproteinase inhibitors containing a heterocyclic P2 P3 Bioorg. Med. Chem. Lett. 6(13):1541-1542 (1996). | |||||
| REF 21 | Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo. J Med Chem. 2001 Aug 2;44(16):2636-60. | |||||
| REF 22 | Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors. Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63. | |||||
| REF 23 | Charge-Triggered Membrane Insertion of Matrix Metalloproteinase-7, Supporter of Innate Immunity and Tumors. Structure. 2015 Nov 3;23(11):2099-110. | |||||
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